The invention relates to viral infections of the eye, and more particularly relates to methods and pharmaceuticals for treatment of viral infections of the eve. In its most immediate sense, the invention relates to treatment of human eye infections caused by Herpesviridae viruses (including but not limited to Human cytomegalovirus, herpes zoster virus, and varicella zoster virus) and Adenoviridae viruses.
Viral diseases of the eye can have significant consequences. Type 1 herpes simplex virus can cause conjunctivitis and keratitis, Human cytomegalovirus can cause retinitis, adenovirus types 8, 19, 29, and 37 can cause epidemic keratoconjunctivitis, and adenovirus types 3, 4, and 7 can cause pharyngoconjuctival fever. Herpes zoster virus (HZV), a member of the Herpesviridae family, can cause severe eye disease when affecting the trigeminal area. Herpes zoster ophthalmicus, a severe form of acute herpes zoster, results from the reactivation of varicella zoster virus (VZV) (another member of the Herpesviridae family) in the trigeminal (fifth cranial) nerve. Any branch of the nerve may be affected, though the frontal branch within the first division of the trigeminal nerve is most commonly involved. This frontal branch innervates nearly all of the ocular and periocular structures. Herpes zoster ophthalmicus at this particular location can lead to blindness and requires a fast and effective therapeutic approach.
Human cytomegalovirus (CMV) is another member of the Herpesviridae family. At least 60% of the US population has been exposed to CMV, with a prevalence of more than 90% in high- risk groups (e.g., unborn babies whose mothers become infected with CMV during pregnancy, people with HIV, and transplant recipients).
CMV retinitis is one of the most common opportunistic infections in persons with AIDS or pharmacologically induced immunosuppression. Individuals with CMV retinitis typically exhibit a progressive decrease in visual acuity, which may progress to blindness. Long-term CMV treatment is necessary to prevent retinitis relapse.
Immune reconstitution syndrome (IRIS) is reported in 16-63% of HIV-infected patients with CMV retinitis following the initiation of HAART (Highly Active Antiretroviral Treatment). CMV IRIS may manifest as painless floaters, blurred vision, photopia, decreased visual acuity, or ocular pain. Some Patients may develop macular edema leading to vision loss or proliferative vitreoretinopathy, spontaneous vitreal hemorrhage, and retinal detachment.
It is known to treat viral eye infections with acyclovir but such treatment is not entirely satisfactory. Topical acyclovir must be applied frequently and causes irritation of the eye. Oral acyclovir causes significant adverse side effects. Other antiviral medications such as gancyclovir, valacyclovir and valgancyclovir are used to treat viral eye infections, and such treatments are also not entirely satisfactory. Gancyclovir is administered intravenously, and therefore cannot be used outside e.g. a hospital setting. Oral antiviral medications such as valacyclovir and valgancyclovir have disadvantages; they are known to cause fever, rash, diarrhea, and hematologic effects (e.g., neutropenia, anemia, thrombocytopenia). In some cases neutropenia may respond to lowering the dose or using drugs that stimulate the production of neutrophils by the bone marrow as granulocyte colony-stimulating factor [G-CSF], or granulocyte-macrophage colony-stimulating factor [GM-CSF]. These toxic effects can be difficult to manage.
It would therefore be advantageous to provide a better method and a better pharmaceutical for treating viral eye infections in humans.
Various enzymatically active ribonucleases, including ranpirnase and other proteins that are highly homologous to it, are known to have antiviral activity, and to have activity against viruses in the Herpesviridae family (specifically including but not limited to Herpes simplex virus types 1 and 2 and Human cytomegalovirus) and also against type 2 adenovirus. However, proteins are known to be highly irritating to the eye due to an intense inflammatory response mediated by T-cells. For this reason, although ranpirnase and other related proteins have been investigated for use against various viral infections, they have not been investigated for use against viral infections of the eye.
Despite the expectation that proteinaceous ranpirnase would cause irritation in the eye, irritation of topically applied ranpirnase in the eye was studied in a rabbit model. In this experiment, ranpirnase was demonstrated to be non-irritating as determined using the Globally Harmonized System of Classification Evaluation Criteria and the European Economic Community Ocular Evaluation Criteria. This was a remarkable result, because administration of a foreign protein to the eye can produce corneal irritation. As a result, ranpirnase and other proteins that are highly homologous to it are expected to be useful in treating viral infections of the human eye.